Neuropeptide Y (NPY), together with certain of its receptors, undergoes profound changes in expression after peripheral tissue injury and is thought to modulate pain in animals. However, the clinical significance of the NPY system in modulating pain in humans is unknown. We propose a series of clinical studies directly testing the hypotheses that, in humans, NPY and its cognate receptors undergo altered expression in inflamed tissue, and act in the periphery to alter spontaneous pain and mechanical allodynia. Our research strategy takes advantage of a common form of pain associated with inflammation, neuronal degeneration and neuroplasticity: odontalgia (toothache) with pulpal necrosis. Pulpal necrosis produces a degeneration of pulpal neurons innervating the inner tissue of the tooth (i.e., the pulp), with a simultaneous sprouting and up-regulation of NPY in neurons innervating the outer tissue of the tooth (i.e., the periodontal ligament around the root). This effect is similar to that seen in certain chronic pain conditions with respect to NPY plasticity. [unreadable] [unreadable] Specific Aim 1: Characterize the effects in humans of inflammation and neuronal degeneration on peripheral levels of NPY and related Y receptors (Y1, Y2, Y5) in periradicuIar tissue surrounding the roots of teeth. [unreadable] [unreadable] Specific Aim 2: Determine whether NPY inhibits neurosecretion of substance P from peripheral terminals of capsaicin-sensitive neurons innervating normal versus inflamed human periradicular tissue. [unreadable] [unreadable] Specific Aim 3: Determine whether NPY is analgesic and/or anti-allodynic in patients experiencing spontaneous pain and mechanical allodynia in a condition of inflammation with neuronal degeneration. [unreadable] [unreadable] Specific Aim 4: Evaluate whether population characteristics are associated with altered pain reports. First, determine whether patients with the C1128 polymorphism of the PreProNPY gene, characterized by increased peripheral NPY levels, report less pain. Second, determine whether ethnic/cultural factors associated with an underserved minority population (Hispanics) are associated with altered pain reports. Collectively, these studies have scientific and medical/social relevance: These integrated studies evaluate NPY modulation of clinical pain at behavioral, biochemical and genetic levels using a clinical pain disorder that permits standardized tissue collection and biochemical analyses. Odontalgia, a condition afflicting > 20 million Americans, is the most common form of orofacial pain (Lipton et al., 1993), and is an under-studied pain disorder. Moreover, our study population in South Texas permits secondary analyses of a potentially underserved population (predominantly Hispanic) that is at risk for caries-induced pulpal necrosis and pain. [unreadable] [unreadable]